For well over twenty years, thermometric assessment of the human female breast surface has been under investigation as a tool in the armamentarium of those concerned with the detection and treatment of breast cancer.
GB 1,492,803 (expired) and U.S. Pat. No. 4,055,166 (expired), both granted to Simpson and Green and of substantially identical content, describe a garment which is a brassiere upon and within which is mounted a plurality of sensors for the purpose of measuring breast temperature over the menstrual cycle. They referred to a menstrual cycle of breast heat amounting to a variation in surface temperature of about 1.degree. C. which is maximal about 3 days before the onset of menstruation. In the preamble, it is made clear that the intention is to detect the presence of actual cancers based on the observation that areas adjacent to a cancerous growth may be "slightly warmer (say 1 or 2.degree. F.) than unaffected areas of the other breast" and that comparison of the 24 hour temperature variation (circadian variation) between normal and cancerous breasts have shown clear differences in time structure.
These authors make an important structural distinction between their brassiere device and the earlier breast surface measurements which had been made in hospital environments with sensors fixed on the skin. They taught the provision of a garment which would allow temperature measurements to be recorded over relatively long periods while the subject lives normally. They provide "apparatus for measuring surface temperatures at points in the region of the human body, including a garment having a plurality of temperature sensors located therein at spaced apart positions, and means for so storing signals representing output signals from the sensors that the relationship of each signal time of occurrence can be retrieved".
In particular, they indicate a preference for the storage means to be mounted on the garment. According to Claim 1 of U.S. Pat. No. 4,055,166, the garment and the means for storing signals are integral,. In Claim 1 of GB 1,492,803 the apparatus includes a garment and Claim 4 and various other dependent Claims describe a brassiere which includes sampling and storage means being integral with the brassiere.
Simpson and Green make it clear that, in relation to measurements of temperature on the breasts, the garment may be a brassiere. They teach a brassiere for measuring surface temperatures of the breasts at predetermined points, including a plurality of temperature sensors positioned in each cup of the brassiere the sampling and storage means being integral with the brassiere.
Their underlying contention is that "The circadian rhythm of breast temperature is regarded as normal feature of the mammary tissue differentiation--a response possibly of a target organ to tides of hormones in the circulation (e.g., 24-h variations in prolactin; menstrual variations in oestrogen). Consequently alterations of the circadian rhythm characteristics occur in breast pathology of which cancer is one example. In this situation the rhythm is sometimes absent and often of altered level and phase. It follows that monitoring breast temperature rhythm over daily and perhaps monthly intervals will be valuable in detection and characterization of disease, e.g., cancer." From this and other statements in the specification it is clear that these authors did not contemplate the application of their invention in the assessment of the future risk of developing cancer and that it was limited to detection of and characterizations of actual lesions.
The Simpson and Green patents teach a brassiere fitted with temperature sensors positioned at points where tumors have been shown to occur most frequently--at one, two and three o'clock, over the nipple and at nine o'clock on the left breast, and on the right breast there is a similar concentration of sensors over the upper outer quadrant, that is at nine, ten and eleven o'clock with a sensor over the nipple and one at three o'clock. They do contemplate different positioning of the sensors and that a different number may be deployed.
What is quite clear, however, is that their device as described, is a garment fitted with temperature sensors and having means for storing signals from the sensors included with or integral with the garment. It is also quite clear from the detailed descriptions and claims that when the apparatus is to be used on the human breast, the garment is to be a brassiere. They also clearly describe, in Claim 6 of each patent, the use of a heat shield to prevent outward heat flow through the sensor.
Simpson has since suggested that the device, which is the subject of the test described in the two patents, is subject to `noise` and that this is due to other vasomotor phenomena. He has suggested that "The problem with the method is not the signal, but the noise from these sources." Sir James Young Simpson Memorial Lecture, J. R. Coll. Surg. Edinb., 41, June 1996. He goes on to suggest that future developments could include Doppler ultrasonography applied to the internal mammary artery and volumetric analysis of the breast and its component tissue using magnetic resonance imaging.
In the source quoted above, Simpson makes it clear that his developments are nowadays directed at trying to predict, from temperature measurements, which breasts may develop cancer later.
Although Simpson and Green appear to have been the first workers to make a serious attempts at detecting breast cancer by observing breast surface temperatures, theirs is not the only work. Detectors for actual cancer lesions based on breast surface temperature are still being developed and this is somewhat surprising since most authorities believe that tumors large enough to find by this method are already likely to be have progressed so far as to carry with them fatal consequences.
One example is BreastAssure.TM. made in the U.S.A. by HumaScan Inc of Cranford, N.J. The makers claim that this device is the subject of two U.S. patents which expired on May 22, 1998 and a Canadian patent expiring on Aug. 24, 1999; these are all believed to be to Z. L. Sagi. Financial literature on the company states the product "consists of a pair of mirror-image, non-invasive, lightweight, disposable soft pads, each of which has three wafer-thin segments containing columns of heat sensitive chemical sensor dots that change color from blue to pink reflecting an 8.5.degree. temperature range from 90.degree. to 98.5.degree. F. When placed over a woman's breasts, inside her brassiere for a period of 15 minutes, the device registers skin temperature variations due to heat conducted from within the breast tissue to the surface of the skin. By comparing the mirror-image temperature differences between the two breasts registered by the device, the physician can objectively quantify if there is abnormal unilateral breast thermal activity, which is considered significant if there is a 2.degree. F. or more temperature difference between each breast in the same mirror-image location. Based on clinical studies at major medical centers, the threshold tumor size that resulted in significant skin temperature differences detectable with the device was as small as 5 mm in size." It may be worth noting that, according to some authorities, cancers of this size may well have already metastasized. Other experts to whom I have spoken doubt whether 15 minutes is an adequate time for any device placed on or over the breasts to equilibrate with breast temperature on a consistently reliable basis.
The manufacturer claims that according to industry sources, the majority of breast tumors are, on average, at least 15 mm or larger before they are palpable by most experienced clinicians. Literature which I have seen suggests that 15-20 mm is the range in which most become tumors become palpable.
Another recent entrant to this field is Biofield Inc of Roswell, Ga., U.S.A., with its ALEXA.TM.1000 system. According to material released by the company onto the Internet, this employs single-use sensors and a measurement device to analyze changes in cellular electrical charge distributions associated with the development of epithelial cancers such as breast cancer. Sensors are arranged on the skin surface in and around the quadrant of the breast where a suspicious lesion has been identified and in corresponding locations on the asymptomatic breast. Sensor readings are measured and analyzed using a pre-programmed algorithm. The technology is claimed to be based on the observation that epithelial cancers are characterized by uncontrolled recurrent cell proliferation of rapid cell division. As these cells divide, an electrical charge is released. This results in a disruption, or depolarization, of the charge distribution found in normal epithelial tissue. Moreover, the depolarization appears to be progressive as cell transformation and carcinogenesis occur. It is claimed that this depolarization is measurable at the skin surface in the form of electrophysiological differentials. The final output is a single numerical and objective value, from 1 to 30. The result of this test is claimed to provide an indication of the proliferation level, which is related to the probability as to whether a lesion is malignant or benign. The manufacturer claims that a task force sponsored by the European School of Oncology has reported on the measurement of electropotentials from the breast as a possible method of detecting breast cancer. This report summarizes the background and early results and suggest that this technique may have a role in the diagnosis of both palpable and non-palpable breast lesions. U.S. Pat. Nos. 5,427,098; 5,560,357; 5,415,164; 5,217,014; 5,320,101 and 5,099,844 all appear to relate to this technology. I have been unable to verify these claims from enquiries made with the European Institute of Oncology, which is a current trial center for the instant invention.
Lifeline BioTechnologies Inc, another U.S. company, has two products which are claimed to increase the chance of finding potential breast cancers at an early stage. The KELLY MONITOR is a detection aid for early breast cancer apparently intended for use as a non-invasive complement to mammography. It consists of sensors and a small portable data storage unit, worn for up to forty-eight hours in order to capture temperature patterns which are stored for later analysis. The device dynamically monitors the physiologic activity of the breast by means of circadian rhythm analysis. This monitor uses a sixteen sensor array: seven for each breast, one for the sternum, and one to measure ambient temperature and, like the Simpson and Green disclosure, calls for placement determined by occurrence data for breast cancer. This product uses a proprietary template for identical placement on each breast. The manufacturer's literature claims to use sensors which are considered "interchangeable", eliminating the need for insulation, adjustable resistors, and continued calibration. This commercial claim appears to be directed in a negative manner at the Chronobra.TM., a device based on Simpson and Green's patents which does require the use of calibration and trimming resistors. It is not clear whether this product is the subject of either an issued patent or a patent application.
Unlike the other devices and products hereinbefore described, the FIRST WARNING.TM. product is claimed to identify women who will eventually develop breast cancer and to be a `Risk-Marker`. The literature indicates that during the test, a custom-designed breast temperature sensor is integrated into a cup insert for use with the patient's brassiere, and she will be directed to place the sensors directly within her brassiere and thus on her breast. The patient would be required to wear the device for ninety minutes each night. The sensor is intended to measure surface temperature over the breast area for each breast throughout this period. The inserts are apparently presented in several sizes to fit the wide variation in breast sizes in the female population. According to the literature, each sensor will detect the unique temperature patterns of the breast. The sensors are described as connected to a miniature storage device which is worn concealed under the clothing. The literature indicates that at the conclusion of the test, the device is plugged into a data storage unit which is small enough to be placed on a bedside table. The data is transferred to the base and the portable unit is recharged. An additional requirement described is for a sample of saliva to be taken on a daily basis. The saliva is placed in a small vial and stored in a refrigerator in a special calendar/date related container until the test concludes. The entire test lasts for thirty days. The results are then analyzed using proprietary techniques to assess the risk factor for the patient. The company claims that traditional statistical techniques are not accurate enough in their discrimination of the data. The ultimate result is an indication of high or low risk. The product is believed to the subject of a U.S. patent application.
The practicality of this test seems to be questionable at least. It has to be done over thirty days and thus requires an enormous level of compliance in today's fast-moving world where many women do not have well ordered lives which allow them to be constantly at home. This test also has to be done for ninety minutes each night, followed by a procedure to re-charge the monitor; it is surely rather likely that the patient would fall asleep. The most limiting factor, however, is likely to be the sheer cost of 30 hormonal assays for each patient. On top of this is the question of available laboratory capacity to carry out the tests--on the basis of the manufacturer's own figures, they hope to generate a level of business per `developing family practice` which would produce a laboratory load of 3,100 hormone assays.
With the exception of the last product described, all prior art items which I have been able to find may be called breast cancer detection aids. As such, their use is limited, since any patient who already has cancer has a reduced risk of survival and a certainty of morbidity. On the other hand, any patient who tests negative, is only negative on the day of the test and has no idea of her future risk status.
Since most authorities now accept that about 1 in 12 women in Europe and maybe as many as 1 in 10 in the U.S.A., dies from breast cancer and up to 1 in 8 may develop the disease at some point in their lives, it would clearly be of enormous benefit to be able to identify which women are at risk and which not. By such a means of risk-assessment, very great relief from stress could be imparted to the majority of women. Even women found to be at risk would be much better off since the health care system, whether public or private insurance based, would be able to release funds to enhance their surveillance, implement better avoidance strategies (perhaps involving diet and nutritional supplementation) and treat them better, should the disease eventually supervene. I estimate that in the UK alone, having an effective means for positively identifying those who are at risk and three quarters of those who are not at risk, would save .English Pound.1.8 billion per annum, as well as avoiding a vast amount of human misery.
Clearly, there is room for substantial improvement in the management of breast cancer since the long term survival prospects, following diagnosis, are still not very encouraging, barely exceeding 50%. Mass campaigns directed at self-examination are not very successful since, even when regularly practised, women who find lumps which turn out to be malignant upon biopsy generally detect these at a size which is lethal. This is particularly so in young women with dense breast tissue.
It may be that today's limited success in treating this disease is partly due to the failure to recognise pre-cancerous states in mammary tissue as a whole. The investigation, observation and tracking of these states would allow earlier diagnosis and would also permit potential intervention strategies to be exploited perhaps with marked effects on ultimate survival rates.
Work published by Simpson and others, well after the date of his patents, includes comparative microscopy data in cancer-associated breasts and age-matched normal breasts showing a gross excess of focal hyperplasias in pre-menopausal cancer-associated breast tissue. Additionally, epidemiological data are consistent with this finding in that such tissue is subject to a 6-fold increased risk of further primary carcinogenesis. In addition, it is now known that premenopausal mammary tissue goes into a monthly pregnancy rehearsal with glandular proliferation and increased blood supply. These phenomena have been shown to produce a luteal heat cycle which produces a variation in breast surface temperature of about 1.degree. C. in normal women (probably not at risk of cancer). Women with cancer-associated breasts exhibit only up to about half this amplitude. The pattern of temperature rise is also different insofar as the temperature rise curve in cancer-associated breasts is relatively steady and peaks earlier in the menstrual cycle than in normals. Normals exhibit a high correlation with and dependence upon endogenous progesterone levels during the luteal phase.
The differences in breast temperatures between `normal` women and clinically normal women with cancer-associated breasts, measured during the luteal heat cycle, are maximal during the few days just after ovulation. Breast temperature variations may be associated, at least in part, with abnormal breast arterial blood flows at particular phases of the menstrual cycle. Significantly increased blood flow commences at the start of the luteal phase, some fourteen days prior to menses. The blood supply of the breast is from the axillary artery via the lateral thoracic and acromio-thoracic branches and also from the internal mammary (thoracic) artery via its perforating branches. In the female, the branches of the second, third and fourth intercostal spaces give branches to the breast which vary in size under hormonal bombardment. Thus although the contribution to overall elevation in breast temperature may be greater by some arteries than others, all exhibit a menstrual cycle of breast blood flow and all contribute to the breast luteal heat cycle.
In any system or device for breast surface temperature measurement which is to have broad applicability for mass screening of populations, great attention has to be given to practicability. Any such entity which consumes large amounts of time in setting up will be unacceptable.
For this reason, the physical attachment of sensors to the breast surface of subjects has not proven popular. The need to apply each sensor separately, usually with adhesive tape, is not only time consuming but has obvious disadvantages for the subject at the time of removal. There is also the problem of ensuring that individual sensors do not become detached as a result of traction on cable connecting means employed to deliver the signal to whatever means is employed for temperature data collection.
The use of a sensor array, integral with a brassiere, this garment also having means for carrying a data logging device, is apparently, the preferred implementation of the Simpson and Green utilities. This device has the name Chronobra.TM. and Simpson has published on this in the lay press as recently as September 1997. It is clear from other publications on this device that, although it has some functionality, there are inherent problems of poor signal, intermittent signal and sometimes a complete absence of signal, logged from certain individual sensors suggesting poor and inconsistent contact between these and the breast surface.
Analysis of the device, an example of which I have obtained, suggests that the problems are unlikely to be truly electrical but are related to the structure and mechanics of the device. The manner in which thermal sensors and the garment are integrated involves the use of a sewn-in lining pad made of stiff material and provided with a plurality of perforations. A plurality of thermal sensors is each encapsulated within in a thick moulding of silicone material which is in the shape of a cylindrical plug which is `T` shaped in cross-section, each sensor being located in the `leg` of a `T`. The sensor mouldings are disposed between the perforated lining pads and the cups of the brassiere. Each perforation in the lining pad accommodates the leg portion of one thermal sensor moulding so as to present it to the breast surface.
I have measured the thickness of the silicone mould material disposed about a number of sensors and in no case was this less than 2.0 mm. However, the least thickness measured at the end of a moulding over that surface of the sensor directed towards the breast was 3.1 mm and in some cases over 4.0 mm. Since silicone rubbers are highly effective insulating materials with poor thermal conductivity it is certain that this arrangement will lead to reduced effectiveness and possibly to repeated low readings. Simpson and Green's disclosures call for insulating means to prevent heat loss and this may be why they employed a large plug of the selected material behind the sensors. However, to employ such a material over the face of the active thermal sensing element suggests a fundamental misunderstanding of the principal aim at hand. This is the measurement of small variations in temperature of a target in an ambient environment, the temperature of which is not vastly different from the target itself. Under these circumstances, the principal aim is only likely to be met either when there is no barrier at all or, if there is one, it has high thermal conductivity and minimal thickness.
Further analysis of the subject Chronobra.TM. device, both on and off subjects, suggests other reasons why instances of intermittent or absent signal are encountered. First, the integral construction of the sensor array and brassiere called for by the Simpson and Green patents and embodied in the use of a lining pad, leads to a rather rigid cup construction which resembles a rounded modified cone. In most women, the breast surface is profoundly convex on the lower aspect and somewhat concave on the superior aspect. Such a mis-match of profiles explains why, in a number of cases, the sensor mouldings of the upper aspect of the cups do not come into contact with the superior breast surface at all. Such a brassiere must, of course, be available in all rational sizes if a general population is to be tested. This inevitably increases the cost and level of inconvenience associated with the test. Mounting the data logging device on the brassiere--which reads for the Simpson and Green patents--between and below the cups, introduces traction on the brassiere and exacerbates the non-contact problem by pulling the upper surfaces of the cups away from the breast surfaces. Each fine, twisted pair of sensor connecting leads extends from the sensor to the data logging device separately and without further protection. This not only makes for an untidy appearance but also increases the risk of tangling and traction on individual sensors. Finally, this device does not use any form of true calibration and therefore it cannot be argued that the output from the sensors represents accurately any particular absolute temperature.